Sepsis is a serious infectious inflammatory syndrome that develops when the initial host response fails to contain the infection. The mortality associated with sepsis remains unacceptably high and is still over 25% among approximately 750,000 patients annually in the US alone. Worldwide, the yearly incidence of sepsis and severe sepsis is estimated at an astounding 31 million and 24 million cases. Many mediators of sepsis have been identified, and many clinical trials have tested the efficacy of targeting these molecules and their mechanisms, but with one short-lived exception, none of these has resulted in an effective and specific treatment for sepsis. These data clearly indicate an unmet need for therapeutic options in sepsis and suggest that new targets, pathways and ideas need to be examined and existing paradigms need to be refined. Neutrophils are a fundamental component of the innate immune response and essential for microbial containment and eradication for sepsis survival. Downregulation of the innate immune response has been described to have adverse outcomes in preclinical and clinical sepsis. However, molecular mechanisms that suppress and dysregulate innate host responses have yet to be clearly defined, and this gap in knowledge represents one of the major barriers to therapeutic advances in the field. Our preliminary studies suggest that syndecan-1, a major cell surface heparan sulfate proteoglycan (HSPG), promotes severe infections in sepsis by inhibiting neutrophil recruitment to sites of infection and by inhibiting extracellular killing mechanisms of neutrophils in a heparan sulfate (HS)-dependent manner. Unlike other means of neutrophil suppression, syndecan-1 alters the efficacy of neutrophil migration prior to the onset of its journey to infection sites. This proposal will examine the hypothesis that syndecan-1 is a critical factor that regulates innate immune suppression in sepsis in 3 specific aims. Aim 1 will define the structural features that enable syndecan-1 HS to promote sepsis. Aim 2 will explore the biological mechanisms of how syndecan-1 suppresses innate immune responses in sepsis. Aim 3 will elucidate the septic pathways that lead to the shedding of syndecan-1 ectodomains and determine the significance of this mechanism in the progression of sepsis. Through these studies, the culminating goal of this proposal is to uncover previously unknown fundamental functions of syndecan-1 in sepsis and to increase our understanding of molecular and cellular pathways that are central to innate immune suppression in sepsis.